The present invention relates to carboxylic acid derivatives. More specifically, the present invention relates to a carboxylic acid derivative of formula (I) 
wherein all symbols are as hereinafter defined, a process for the preparation thereof and a pharmaceutical agent comprising the same as active ingredient.
Prostaglandin E2 (PGE2) has been known as a metabolite in the arachidonic acid cascade. It has been known that PGE2 possesses cyto-protective activity, uterine contractile activity, a pain-inducing effect, a promoting effect on digestive peristalsis, an awaking effect, a suppressive effect on gastric acid secretion, hypotensive activity, and diuretic activity.
In the recent study, it was found that PGE2 receptor was divided into some subtypes, which possesses different physical roles from each other. At present, four receptor subtypes are known and they are called EP1, EP2, EP3 and EP4 respectively (J. Lipid Mediators Cell Signaling 12, 379-391 (1995)).
Among these subtypes, EPa receptor was believed to be involved in signal transduction of peripheral nerve, control of exothermal reaction in central nerve, formation of memory by expressing in cerebral neuron, vascularization, reabsorption of urine by expressing in renal tubular, uterine contraction, production of ACTH, platelet aggregation. Besides, it was expressed in vascular smooth muscle, heart and gastrointestinal tract also. EP4 recptor was believed to be involved in suppression of TNF-xcex1 production and induction of IL-10 production.
So the compounds which can bind to EP3 receptor and/or EP4 receptor strongly and show the antagonizing activity, are useful for the prevention and/or treatment of diseases induced by excess activation of EP3 receptor and/or EP4 receptor, for example, pain such as cancerous pain, fractural pain, pain following surgical and dental procedures; allodynia, hyperalgesia, pruritus, urticaria, atopic dermatitis, contact dermatitis, allergic conjunctivitis, various symptoms by treating with dialysis, asthma, rhinitis, sneeze, urinary frequency, neurogenic bladder, urinary disturbance, ejaculatory failure, defervescence, systemic inflammatory response syndrome, learning disturbance, Alzheimer""s disease, cancer such as formulation of cancer, growth of cancer and metastasis of cancer; retinopathy, patch of red, scald, burn, burn by steroid, renal failure, nephropathy, acute nephritis, chronic nephritis, abnormal blood levels of electrolytes, threatened premature delivery, abortion threatened, hypermenorrhea, dysmenorrhea, uterine fibroids, premenstrual syndrome, reproductive disorder, stress, anxiety disorders, depression, psychosomatic disorder, mental disorder, thrombosis, embolism, transient ischemia attack, cerebral infarction, atheroma, organ transplant, myocardial infarction, cardiac failure, hypertension, arteriosclerosis, circulatory failure and circulatory failure induced ulcer, neuropathies, vascular dementia, edema, various arthritis, rheumatism, diarrhea, constipation, disorder of bilious excretion, ulcerative colitis, Crohn""s disease and/or bone diseases such as osteoporosis, rheumatoid arthritis, osteoarthritis, abnormal bone formation; cancer such as formation of cancer, proliferation of cancer, metastasis of cancer to organs and to bones and hypercalcemia induced metastasis to bones of cancer; systemic granuloma, immunological diseases such as ALS, multiple sclerosis, Sjoegren""s syndrome, systemic lupus erythematosus, AIDS; allergy such as conjunctivitis, rhinitis, contact dermatitis, psoriasis; atopic dermatitis, asthma, pyorrhea, gingivitis, periodontitis, neuronal cell death, Alzheimer""s disease""s disease, pulmonary injury, hepatopathy, acute hepatopathy, nephritis, renal failure, myocardial ischemia, Kawasaki disease, scald, ulcerative colitis, Crohn""s disease, multiple organ failure etc. Moreover, EP4 is thought to be involved in sleeping disorder and platelet aggregation, so the compounds are considered to be useful.
The present inventors have energetically studied to find the compound which bind to PGE2 receptor, EP3 and/or EP4 receptor specifically and show an inhibitory activity against it, to find out that the carboxylic acid derivatives of formula (I) achieve the purpose and completed the present invention.
This invention was relates to
(1) a carboxylic acid derivative of formula (I) 
wherein R1 is COOH, COOR6, CH2OH, CONHSO2R7 or CONR8R9,
R6 is C1-6 alkyl, (C1-4 alkylene)xe2x80x94R16,
R7 is (1) C1-4 alkyl, or (2) substituted by 1-2 of substitutes selected form C1-4 alkyl, C1-4 alkoxy and halogen atom or unsubstituted (2-1) C6-12 mono- or bi-carbocyclic ring or (2-2) 5-15 membered mono- or bi-heterocyclic ring containing at least one of hetero atom selected from nitrogen, oxygen and sulfur, or (3) C1-4 alkyl substituted by the above substituents or unsubstituted carbocyclic ring or heterocyclic ring,
R8 and R0 each independently, is hydrogen or C1-4 alkyl,
R16 is hydroxy, C1-4 alkoxy, COOH, C1-4 alkoxycarbonyl, CONR8R9,
A is C1-6 alkylene or xe2x80x94(C1-3 alkylene)wxe2x80x94Gxe2x80x94(C1-3 alkylene)xe2x80x94,
w is 0 or 1,
G is oxygen, sulfur or NR10,
R10 is hydrogen or C1-4 alkyl,
R2 is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, halogen atom, CF3, cyano, nitro, hydroxy, NR11R12, CONR11R12, SO2NR11R12, or xe2x80x94S(O)xxe2x80x94(C1-6)alkyl,
m is 0, 1 or 2, when m is 2, then two R2 may be same or difference,
R11 and R12 each independently, hydrogen or C1-4 alkyl,
x is 0, 1 or 2,
B ring is C5-7 mono-carbocyclic ring or 5-7 membered mono-heterocyclic ring containing at least one of nitrogen, oxygen and sulfur,
R3 is hydrogen or C1-4 alkyl,
R4 is (1) C1-8 alkyl, (2) C2-8 alkenyl, (3) C2-8 alkynyl, (4) C3-6 cycloalkyl, (5) hydroxy, (6) C1-4 alkoxy, (7) C1-4 alkoxy(C1-4)alkoxy, or (8) C1-8 alkyl substituted by 1-2 of substitutes selected from halogen atom, hydroxy, C1-6 alkoxy, C1-4 alkoxy(C1-4)alkoxy, phenyl and C3-6 cycloalkyl,
R5 is substituted by 1-2 of R13 or unsubstituted C5-10 mono- or bi-carbocyclic ring or 5-10 membered mono- or bi-heterocyclic ring containing at least one of nitrogen, oxygen and sulfur,
R18 is C1-6 alkyl, C1-6 alkoxy, halogen atom, CF3, cyano, C1-4 alkoxy(C1-4)alkyl, phenyl, phenyl(C1-6)alkyl, xe2x80x94(C1-4 alkylene)y-Jxe2x80x94(C1-8 alkylene)xxe2x80x94R14, benzoyl or thiophenecarbonyl and two R13 may be same or difference,
y is 0 or 1,
z is 0 or 1,
R14 is phenyl or pyridyl,
J is oxygen, S(O)t or NR15,
t is 0, 1 or 2,
R16 is hydrogen, C1-4 alkyl or acetyl;
or non-toxic salts,
(2) a process of the preparation thereof, and
(3) a pharmaceutical agent comprising the same as active ingredient.